Enhancement of urogenital function

ABSTRACT

An exemplary method of treating a urologic symptom includes administering a daily dose of creatine to an individual wherein the daily dose of creatine lies in a range from about 0.35 mg to about 3.5 mg per kilogram body weight. Such an exemplary method may further include administering a dose of a compound that inhibits phosphodiesterase (e.g., at a time less than approximately 4 hours prior to sexual activity). Other exemplary methods, compounds, compositions, etc., are also disclosed.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/743,086, entitled “Enhancement of Urogenital Function”, filedDec. 30, 2005, to Hander, the specification of which is incorporatedherein by reference.

TECHNICAL FIELD

The subject matter disclosed herein generally relates to dose deliverysystems, compounds, compositions and methods for enhancing urogenitalsystem function.

BACKGROUND

Local or systemic conditions can impair urogenital system function.Consider benign prostatic hyperplasia (BPH), which affects thewalnut-sized prostate gland that surrounds the proximal urethra (theduct that drains the bladder). BPH commonly causes urinary tractsymptoms secondary to bladder outlet obstruction. Bladder outletobstruction has both a static component (structural and local) and adynamic component (neurogenic and systemic). The static component is dueto enlargement of the prostate gland, which commonly results incompression of the urethra and obstructed flow of urine from thebladder. The dynamic component is due to increased smooth muscle tone ofthe inner (involuntary) bladder neck sphincter. The dynamic component isat least partially regulated by alpha adrenergic sympathetic nervoussystem tone. Alpha adrenergic tone is mediated by way of alphaadrenergic synaptic receptors as well as by various second messengerpathways, including cyclic 3′-5′ adenosine monophosphage (cAMP). Smoothmuscle tone of the inner sphincter may also depend on extra-andintracellular Ca²⁺ stores. Excessive inner sphincter smooth muscle toneresults in bladder neck dysfunction.

Evaluation of BPH related urinary tract symptoms often includes use ofan assessment test such as the International Prostate Symptom Score(I-PSS). A subject's I-PSS score is based on seven questions related tourination (incomplete emptying, frequency, intermittency, urgency, weakstream, straining, and nocturia). The nocturia question asks: “Over thepast month, how many times did you most typically get up to urinate fromthe time you went to bed at night until the time you got up in themorning?” Patients with symptomatically significant BPH get up tourinate more times per night than is considered normal. Normal nocturnalurination frequency is zero or once. The symptom nocturia may also beconsidered to refer to difficulty initiating urine stream and completebladder emptying during sleep hours.

Common treatments for BPH related urinary symptoms includeadministration of alpha adrenergic antagonists (alpha blockers) such astamsulosin hydrochloride and terazosin hydrochloride. Alpha blockersdecrease involuntary bladder sphincter tone of the prostatic urethra topromote free flow of urine and decreased urinary symptoms. Alphablockers act on the dynamic component of bladder outlet obstruction. Acommon side effect of alpha blocker treatment is retrograde ejaculation.

Another common treatment for BPH related urinary symptoms acts on thestatic component of bladder outlet obstruction. It involvesadministration of the enzyme inhibitor finasteride. Finasteride is acompetitive inhibitor of the enzyme 5α-reductase, which is responsiblefor the conversion of testosterone to dihydrotesterosterone in theprostate gland. Dihydrotestosterone appears to be the major mitogen forprostate growth, and agents which inhibit 5α-reductase inhibit theprogressive growth of the prostate which is characteristic of BPH. Itthereby inhibits the progressive impairment of urine flow through theprostatic urethra with advancing age. Only men who already havesignificant prostate symptoms are likely to be treated with finasteride.Recognized side-effects of finasteride, experienced by around 6%-19% ofusers, include erectile dysfunction, and less often gynecomastia (breastgland enlargement).

The treatment of prostate symptoms as noted above are known to interferewith sexual functions such as penile erection and ejaculation. There arealso physiologic interactions between the male reproductive and urinarysystems. For example, it is normally not possible for males tovoluntarily urinate while having an erection. Analogously it may be thatnocturnal erections serve to prevent involuntary nocturnal bladderemptying. Both BPH and erectile dysfunction occur with increasingfrequency over the age of fifty in men. It is not established whetherthere is a casual connection between these two common urogenitaldisorders of aging men. Various exemplary compounds, compositions andmethods described herein aim to address urinary system and/or malereproductive system health and disorders. They may also address certainurinary system disorders in females.

DETAILED DESCRIPTION

The following description includes the best mode presently contemplatedfor practicing various described implementations. This description isnot to be taken in a limiting sense, but rather is made merely for thepurpose of describing the general principles of the variousimplementations. The scope of the described implementations should beascertained with reference to the issued claims. FIGS. 1A, 1B and 1C arereferenced further below and illustrate dose delivery systems.

As mentioned in the Background section, prostate conditions such as BPHcan alter normal urinary system functions and even reproductive systemfunctions. In older men, a traditional association exists between BPH,prostatic urethral obstruction and urinary symptoms. As describedherein, exemplary methods include administration of a compound orcomposition to alleviate or reduce urinary flow symptoms, especially forpatients diagnosed with BPH. In addition, such methods can increasefrequency of nocturnal erections, an indicator of normal reproductivesystem function. Consequently, various exemplary methods discussedherein can enhance quality of life by addressing urinary symptoms andsexual function.

An exemplary method includes ingestion of a compound that includescreatine. The preferred compound is phosphorylated creatine, whichincludes creatine monophosphate or phosphocreatine. Creatine is anitrogenous amine. Normal daily dietary intake of creatine from anomnivarious diet approximate 1 g. Exogenous dietary sources of creatineinclude meat, fish, and other animal products, but it may also be formedendogenously in the liver, kidney, and pancreas from the amino acidsglycine, arginine, and methionine. The normal daily requirement fromeither exogenous or endogenous sources approximates 2 g to replacecatabolized creatine, which is excreted from the kidneys as creatinine.

Harris et al., “The concentration of creatine in meat, offal andcommercial dog food”, Res Vet Sci., 1997 Jan-Feb;62(1):58-62, reportedconcentrations of creatine (Cr), phosphorylcreatine (PCr) and creatinine(Cn) in a variety of meats, before and after cooking by boiling, in arange of commercially available canned dog foods, in rendered and driedmeat products and in commercially available dry dog foods. Harris et al.noted that none of the samples contained PCr. They also reported thatuncooked chicken, beef and rabbit meat contained approximately 30 mmolkg⁻¹ of Cr. Ox-heart and ox-liver had Cr concentrations of 22.5 and 2.3mmol kg⁻¹, respectively. Canned dog foods had Cr concentrations of 0.5to 2 mmol kg⁻¹. Dried meat samples had Cr concentrations of 90 to 100mmol kg−1 dry weight. In contrast, the Cr concentration of driedrendered meat meal was 3 mmol kg⁻¹ dry weight or less. Dry dog foodscontained 0.5 to 4 mmol kg⁻¹ dry weight of Cr. Harris et al., reportedthat their results indicate that in the canned dog foods, the dried meatsamples and the dried rendered meat meal creatine has been degraded tovariable extents to creatinine.

Based on the study of Harris et al., and the kinetics ofphosphocreatine, it is expected that processed and cooked meats, poultryand fish supply very little phosphocreatine to an individual's diet.

Approximately 120 g of creatine is found in a 70 kg male, 95% in theskeletal muscle. Total creatine (TCr) exists in the muscle as both freecreatine (FCr) and phosphocreatine (PCr). About 60% of the TCr is PCr,and the remainder is FCr. Creatine is an important source of chemicalenergy for muscle contraction because it can undergo phosphorylationthat is both rapid, with the formation of PCr, and reversible, withdonation of the phosphate group to adenosine diphosphate (ADP) to formadenosine triphosphate (ATP). This phosphorylationdephosphorylationreaction, catalyzed by the enzyme creatine kinase, is a rapid source ofhigh-energy phosphate for performing high-intensity, short-durationphysical activity.

Intramuscular supplies of both high-energy phosphagens ATP and PCr arelimited, with the combined total being estimated to sustain veryhigh-intensity exercise for approximately 10 seconds. Theoretically,creatine supplementation could increase [TCr], possibly facilitating thegeneration of intramuscular [PCr] and subsequent ATP formation,prolonging the duration of high-intensity physical activity.

A preferred exemplary compound is phosphorylated creatine. A common formof phosphorylated creatine is phosphocreatine, also known generally ascreatine phosphate or creatine monophosphate and sometimes abbreviatedPCr. Phosphorylate creatine is an important storage form of high energyphosphate, the energy source for muscle contraction. As describedherein, the preferred exemplary compound is typically referred to ascreatine monophosphate. Other forms of phosphorylated creatine may beused as an exemplary compound and appropriate CSUE doses determined, forexample, using stoichiometry and/or comparisons to creatinemonophosphate doses. Another creatine compound is creatine monohydrate.Yet another form of creatine is creatine ethyl ester, or simply creatineester. Theories suggest that the ethyl ester allows for easy absorptionin the intestines and that this form can be taken directly into a musclecell through the cell wall.

Creatine (2-Amino-1,5-dihydro-1-methyl-4H-imidazol-4-one) has amolecular mass of about 131 g/mol. Creatine monohydrate has a molecularmass of about 149 g/mol. Creatine monophosphate, the preferred form of aphosphorylated creatine compound, has a molecular mass of about 210g/mol. For purposes of comparison, 5 g of creatine monohydrate yields4.40 g of creatine, 5 g of creatine monophosphate yields 3.12 g ofcreatine and 5 g of creatine citrate yields 2 g of creatine. Where arange or amount is referenced with respect to one form, conversion toanother form is possible using such relationships or other relationshipsfor yet other forms of creatine.

Creatine use is common among professional athletes and its use hasspread to college athletes and recreational athletes that seek toenhance performance of high-intensity, short-duration exercise. Mostcreatine supplement regimens (CSRs) include a loading dose of 20 g to 30g divided into 4 equal doses for 5 days to 7 days (e.g., approximately0.3 g/kg/day), followed by a 2 g to 3 g per day maintenance dose. Levelsof skeletal muscle creatine return to normal within about 2 weeks to 4weeks after oral supplementation ceases.

As described herein, creatine monohydrate is useful at doses lower than1.8 g per day. For a subject with a body weight of about 75 kg, a 2 gdose of creatine monohydrate (about 1.8 g creatine) corresponds toapproximately 27 milligrams (mg) creatine monohydrate per kg body weight(24 mg creatine). In an example described below, a subject with a bodyweight of about 78 kg ingested 88 mg per day of creatine to improveurologic condition, which corresponds to approximately 1.1 mg ofcreatine per kg body weight. Creatine supplementation for urologicenhancement is referred to herein as CSUE, hence, doses lower than 1.8 gper day of creatine or less than approximately 24 mg of creatine per kgbody weight may be considered CSUE dose levels. Various exemplary CSUEranges are mentioned below that are below 24 mg of creatine per kg bodyweight.

While many athletes use the CSR dose levels to enhance performance ofhigh-intensity, short-duration exercise, conceivably, increased levelsof PCr could reduce reliance on anaerobic glycolysis as a replenishmentsource of ATP, and possibly mitigate the formation of lactic acid andenhance performance in high-intensity, more prolonged exercise tasksapproximating 30 to 150 seconds. However, some reports have linkedcreatine dosage levels used for enhanced athletic performance to weightgain, cramping, dehydration, diarrhea, and dizziness. Creatine maydecrease renal function, but only two case reports of this effect havebeen published (see, e.g., a review article entitled “CreatineSupplementation and Exercise Performance: An Update” by Williams andBranch, J Am College of Nutrition, Vol. 17, No. 3, 216-234 (1998)).

The aforementioned review of Williams and Branch presents a tablesummarizing 31 studies on creatine monohydrate supplementation forenhancing short-term, high-intensity performance. The lowest daily dose,without prior loading, is 3 g per day. The authors of this low dosestudy did not observe ergogenic effect for varsity football and trackathletes. This study suggests that the minimum dosage required for thebenefits discussed herein to treat one or more urologic symptoms is lessthan the dosage required for observation of an ergogenic effect (e.g.,for athletes in competition). Further, the desired benefits discussedherein are, in general, germane to an older population (e.g., older menhaving prostate-related symptoms, erectile dysfunction, or otherurologic symptoms, etc.).

An exemplary method includes providing creatine monophosphate powder andadministering a dose of the creatine monophosphate powder. Other formsof creatine monophosphate are discussed below (e.g., tablet form, etc.).

A trial provided creatine monohydrate as a powder (about 100% creatinemonohydrate) and administered a single dose (approximately 0.1 to 0.2 g)of the creatine monohydrate powder in a solution (about 0.09 to 0.17 gcreatine) approximately 0.5 to 3 hours prior to sleep. Urinaryflow-related symptoms were reduced for the immediate sleep period andfor sleep periods during the following 48 hours. Further, in this trialan increase in nocturnal erections was noted as well as an increase intesticular blood flow as evidenced by palpable scrotal contentenlargement.

In the aforementioned trial, the male subject aged about 57, had ahistory nocturia in the presence of diagnosed moderate prostateenlargement. The subject weighed approximately 80 kg (about 175 lbs).Thus, the dosage was about 0.9 mg of creatine per kg of body weight.Range may vary by individual and prior consumption of a creatinecompound. A general range for CSUE may be from about 0.4 mg creatinemonohydrate to about 4.0 mg creatine monohydrate per kg body weight perday (e.g., about 32 mg to about 320 mg per day for a subject weighingabout 80 kg). As already mentioned, the various trials used creatinemonohydrate powder (about 100%) in solution. Thus, in terms of creatinecontent, the general range for CSUE may be from about 0.35 mg creatineper kg body weight per day (e.g., about 0.4*(4.4/5) mg) to about 3.5 mgcreatine per kg body weight per day (e.g., 4.0*(4.4/5) mg). While dosemay vary from patient to patient, the dose is typically less than thedose for CSR.

Additional trials administered doses of creatine monohydrate in solutionin a range of approximately 0.1 g to approximately 1.0 g over a periodof days (in a loading phase) to the aforementioned male subject and toanother male subject of similar weight (˜85 kg), aged 77. The older malesubject (whose main urinary symptom was frequent urination during theday) was administered a loading phase dose of about 0.25 g (250 mg) ofcreatine monohydrate in solution every 24 hours. Both subjects foundthat, after a loading phase lasting several days, the CSUE dosesufficient to achieve the desired effects could be lowered to about 0.05g (50 mg) to about 0.15 g (150 mg) of creatine monohydrate in solutionevery other day for the younger subject and to about 0.125 g (125 mg) ofcreatine monohydrate in solution every other day for the older subject.In both subjects, symptoms were relieved. The post-loading phase isreferred to herein as a maintenance phase. The dose may vary during themaintenance phase; however, it is generally at least 50% less than thedose used in a loading phase. Both subjects noted that doses of greaterthan 1 g (1000 mg) of creatine monohydrate after the loading phaseproduced less urinary symptom reduction. The younger subject noted thatdoses larger than about 0.25 g (250 mg) of creatine monohydrate in themaintenance phase made initiation of his urine stream at night moredifficult until 24 hours to 48 hours later at which time it improvedthat symptom as it did with lower doses.

In these trials, urinary flow-related symptoms were reduced. In general,for these trials, a CSUE dose at least an order of magnitude less thanthe maintenance dose typically used for athletic reasons (i.e., a CSRdose) reduced urinary flow-related symptoms. For example, a single doseless than approximately 17 g (170 mg) of creatine reduced urinaryflow-related symptoms whereas a typically reported minimum maintenanceathletic dose is 1.2 g (1200 mg) of creatine, which is about an order ofmagnitude higher. Further, the trials with the younger subject showedthat such CSUE doses of creatine increased frequency and duration ofnocturnal erections.

Trial results demonstrated that initial dose of a loading phase wouldrelieve symptoms within 24 hours. However, in various trials, a delay inrelief was experienced that corresponded to the dose size where a largerthan required dose would actually delay relief (e.g. beyond 24 hours toas much as 72 hours). In other words, too small of a dose of creatinewould not relieve symptoms, a range of doses of creatine would relievesymptoms within 24 hours and larger doses of creatine would cause adelay in the relief to beyond 24 hours. Such trials indicate that adosage range exists for relief of symptoms and for timing of the relief.

An exemplary method includes administering loading phase doses of about17 g (170 mg) to about 44 g (440 mg) of creatine per day to a maleweighing about 80 kg for several days up to one month. According to sucha method, if relief of symptoms does not occur within 24 hours of theinitial loading phase dose, then the dose size may be reduced.Thereafter, administration of maintenance phase doses of about 044 g (44mg) to about 0.22 g (220 mg) of creatine per day may occur. These dosesare given as examples and may be differ depending on patient condition,while, in general, the maintenance doses of creatine are less than CSRdoses.

ED and Creatine

According to various exemplary compounds, compositions and methodsdescribed herein, a link exists between nocturnal erectile function andurethral sphincter function. In general, an exemplary composition thatincludes creatine and may be enhanced by including another compound thatpromotes nocturnal erections. Noting, that by itself, in an exemplaryrange of about 028 g (28 mg) to about 0.28 g (280 mg) of creatine perday for an adult male weighing around 80 kg, creatine can increaseincidence of nocturnal erections.

Various pharmaceuticals are presently available to treat a conditiongenerally known as erectile dysfunction (ED) or impotence. ED is asexual dysfunction characterized by the inability to develop or maintainan erection of the penis for satisfactory sexual intercourse regardlessof the capability of ejaculation. There are various underlying causes,such as diabetes, many of which are medically reversible. As notedabove, the 5α-reductase inhibitor finasteride may cause ED as aside-effect.

A class of drugs known as phosphodiesterase type 5 inhibitors (PDE5inhibitors) is used to treat ED. Prescription PDE5 inhibitors includesildenafil (VIAGRA®), vardenafil (LEVITRA®) and tadalafil (CIALIS®);there are normally taken orally. The mechanism operates through blockingthe action of PDE5,which causes cyclic guanosine monophosphate (cGMP) todegrade. cGMP causes the smooth muscle of the arteries in the penis torelax, allowing the corpus cavernosum to fill with blood.

Sildenafil citrate has the formula C₂₂H₃₀N₆O₄S.C₆H₈O₇ and its IUPAC nameis1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazol[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazinecitrate (non-salt form about 474.6 g/mol).

Vardenafil has the formula C₂₃H₃₂N₆O₄S and its IUPAC name is4-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-9-methyl-7-propyl-3,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one(about 488.6 g/mol).

Tadalafil has the formula C₂₂H₁₉N₃O₄ and its official organic name is(6R,12aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1,2:1,6]pyrido[3,4-b]indole-1,4-dione(about 389.4 g/mol).

Part of the physiological process of penile erection involves theparasympathetic nervous system causing the release of nitric oxide (NO)in the corpus cavernosum of the penis. NO binds to the receptors of theenzyme guanylate cyclase which results in increased levels of cGMP,leading to smooth muscle relaxation (vasodilation) in the corpuscavernosum, resulting in increased inflow of blood and an erection.

Sildenafil is a potent and selective inhibitor of cGMP specificphosphodiesterase type 5 (PDE5) which is responsible for degradation ofcGMP in the corpus cavernosum. The molecular structure of sildenafil issimilar to that of cGMP and acts as a competitive binding agent of PDE5in the corpus cavernosum, resulting in more cGMP and better erections.Without sexual stimulation, and therefore lack of activation of theNO/cGMP system, sildenafil should not cause an erection. Tadalafil andvardenafil operate by the same mechanism.

A typical dose range for sildenafil is 25 mg to 100 mg taken once perday between 30 minutes to 4 hours before sexual intercourse. It isusually recommended that a patient start with a dosage of sildenafil of50 mg and then lower or raise the dosage as appropriate. Sildenafil istypically sold in three dosages: 25 mg, 50 mg, and 100 mg. Some patientsmay adjust dose by cutting the pills in half, for example, with a pillcutter.

Vardenafil is available in 2.5 mg, 5 mg, 10 mg, and 20 mg doses in roundorange tablets. The normal starting dose is 10 mg (roughly equivalent to50 mg of sildenafil). Vardenafil is recommended to be taken about 25minutes to about 60 minutes prior to sexual activity, with a maximumdose frequency of once per day. With respect to tadalafil, a 20 mg doseis comparable to a 100 mg dose of sildenafil. Tadalafil tablets areyellow, film-coated, and almond-shaped, and are produced in 5 mg, 10 mgand 20 mg doses and at some doses it can have an extended effect (e.g.,reported 36-hour effect).

As described herein, an exemplary method includes administration ofcreatine and administration of a PDE5 inhibitor. For example, prior tosexual intercourse, a subject may ingest (e.g., orally) 88 mg ofcreatine and an appropriate dose of a PDE5 inhibitor (e.g., 2.5 mg to100 mg depending on circumstances and type of PDE5 inhibitor).

In a trial, the subject aged about 57 years old, ingested approximately88 mg of creatine and about 6.25 mg to 12.5 mg of sildenafil citrate(VIAGRA®) simultaneously at a time prior to sexual intercourse (e.g.,four hours or less prior to sexual intercourse). The subject noted anincrease in the effectiveness of the sildenafil citrate at these lowereddoses.

An exemplary composition includes creatine and sildenafil. Such acomposition may be, for example, in the form of a pill, a liquid, a gel,a patch, a lozenge or a suppository. An exemplary pill includes creatinemonophosphate and sildenafil creatine. Such a pill may include acreatine monophosphate (a phosphorylated creatine) to sildenafil citrateratio in a range of approximately 1:10 to 10:1 (consider, e.g., a 1:10ratio that administers 10 mg PCr to p100 mg sildenafil citrate and a10:1 ratio that administers 250 mg PCr to 25 mg sildenafil citrate).This range of ratios is given as an example as other ranges arepossible. Such ranges may be used for other delivery forms. As noted,tadalafil and vardenafil doses are about 5 times less than the dose forsildenafil. Thus, the example range of approximately 1:10 to 10:1 may beadjusted accordingly (e.g., up to 50:1 for tadalafil and vardenafil,etc.).

An exemplary method provides for reduction of dose size of a PDE5inhibitor. Such a reduction in dose size may allow a patient to reduce aside effect or side effects associated with the PDE5 inhibitor. Inparticular, as administration of an exogenous source of creatine hasbeen shown in trials to increase effectiveness of a PDE5 inhibitor, thedose of the PDE5 inhibitor may be reduced.

Importantly, occurrence of adverse drug reactions (ADRs) with PDE5inhibitors appears to be dose related. Headache is a very common ADR,occurring in >10% of patients. Other common ADRs include: dizziness,flushing, dyspepsia, nasal congestion or rhinitis. Some have reportedsildenafil associated ADRs such as priapism, severe hypotension,myocardial infarction, ventricular arrhythmias, sudden death, stroke andincreased intraonocular pressure. Some have reported ADRs fromsildenafil as include sneezing, headache, flushing, dyspepsia, prolongederections, palpitations and photophobia. Some have reported visualchanges including blurring of vision. The most commonly reported ADRs oftadalafil include headache, indigestion, back pain, muscle aches,flushing, and stuffy or runny nose. Common vardenafil-specific ADRsinclude nausea while infrequent ADRs include: abdominal pain, back pain,photosensitivity, abnormal vision, eye pain, facial oedema,hypertension, palpitation, tachycardia, arthralgia, myalgia, rash, itch,priapism.

Thus, ingestion of creatine can allow for a reduction in PDE5 inhibitordose and thereby reduce an ADR or ADRs. Such an exemplary method mayalso reduce cost per dose of PDE5 inhibitor. Dose reduction of a PDE 5inhibitor through administration of creatine may also reduce a druginteraction between the PDE5 inhibitor and one or more other drugs(e.g., drugs which inhibit or induce CYP3A4, including HIV proteaseinhibitors, ketoconazole, itraconazole, etc.).

A cGMP PDE5 inhibitors may be optionally selected from the followinggroup:

3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dichloro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2)2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

3-ethyl-5-[5-(4-oxidopiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-(2-methoxyethyoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

(+)-3-ethyl-5-[5-(4-ethylpiperazin-1-sulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-one;

3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-(6-methylpyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2(6-methoxypyridin-2-yl)methyl-2,6-dihydro-7H-pyrazol[4,3-d]pyrimidin-7-one;

5-[2-i-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,3-diethyl-2,6-dihydro-7H-pyrazolo[[4,3-d]pyrimidin-7-one;and

5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[1-pyridin-2-yl)ethyl]2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneor a pharmaceutically acceptable salts of one of such compounds. Othercompounds may be used that elevate cGMP levels (e.g., other cGMP PDEinhibitors).

Adamantane Derivatives

Adamantane derivatives include amantadine, memantine and rimantadine.Such compounds may be used in combination with creatine and optionally aPDE5 inhibitor or other compound mentioned herein. Antiparkinsonian andneuroprotective agents amantadine and memantine inhibit responses toN-methyl-D-aspartic acid (NMDA).

Amantadnine (1-aminoadamantane (IUPAC adamantan-1-amine, about 151.25g/mol), sold as SYMMETREL®) is an antiviral drug that was approved bythe Food and Drug Administration in 1976 for the treatment ofInfluenzavirus A in adults. The drug has also been demonstrated to helpreduce symptoms of Parkinson's disease and drug-induced extrapyramidalsyndromes. As an antiparkinsonic it can be used as monotherapy; ortogether with L-DOPA to treat L-DOPA-related motor fluctuations (i.e.,shortening of L-DOPA duration of clinical effect, probably related toprogressive neuronal loss) and L-DOPA-related dyskinesias (choreiformmovements associated with long-term L-DOPA use, probably related tochronic pulsatile stimulation of dopamine receptors). Amantadine hasbeen shown to relieve SSRI-induced anorgasmia in some people, though notin all people. There have been anacdotal reports that low-doseamantadine has been successfully used to treat ADHD. Amantadine is aderivative of adamantane, like a similar drug rimantadine.

While the mechanism of its antiparkinsonic effect is not fullyunderstood, it appears to be responsible for releasing dopamine from thenerve endings of the brain cells, together with stimulation ofnorepinephrine response. Furthermore, it appears to be a weak NMDAantagonist and an anticholinergic.

A trial involving the younger subject (age about 57 years) involvedoccasional administration of about 100 mg of amantadine for fluprophylaxis. The subject noted that such administration correlated withreduction in nocturnal urinary symptoms.

An exemplary method includes treating urologic problems with amantadine.An exemplary method includes treating urologic problems with amantadineand creatine. An exemplary method includes treating erectile dysfunctionwith amantadine and a PDE5 inhibitor, and optionally creatine. In theaforementioned methods that include administration of creatine, theamount of creatine may be a CSUE dose level.

An exemplary composition includes creatine and amantadine (e.g., pill orother form). An exemplary composition includes amantadine and a PDE5inhibitor (e.g., pill or other form). An exemplary composition includescreatine, amantadine and a PDE5 inhibitor (e.g., pill or other form). Inthe aforementioned compositions that include creatine, the amount ofcreatine may be a CSUE dose level.

In a trial, the younger subject (age about 57 years) ingested smallamounts of amantadine along with about 88 mg of creatine. The smallamounts of amantadine were measured by opening a capsule of amantadineand pouring out small amounts. Ten individual administrations used lessthan one 100 mg capsule of amantadine. Thus, the dose of amantadine wasapproximately 5 mg to approximately 10 mg. The subject did not note anyeasily discernable effects on now mild LUTS but did not easilydiscernible sexual effects.

The aforementioned younger subject found that if amantadine (about 5 mgto about 10 mg) and creatine (about 88 mg) were taken shortly beforesexual activity in conjunction with small amounts of VIAGRA® (a quarterof a 50 mg tablet or about 12.5 mg) or LEVITRA® (a quarter of a 10 mgtablet or about 2.5 mg) with excellent results as to erectile function.Normally such small doses of either of the PDE5 inhibitor ED drugs issomewhat marginally effective. The subject noted that all threesubstances (creatine, amantadine and PDE5 inhibitor) seem to workquickly and well together even less than 45 minutes before sexualactivity.

The subject had been using VIAGRA®, LEVITRA® and CIALIS® ED drugs in lowdoses for most conjugal sexual activity for the pas four years. Thesubject noted good results with or without creatine, but somewhat betterwith creatine and excellent with the combination of amantadine, creatineand an PDE5 inhibitor ED drug.

The subject took increasingly small doses of DHEA to enhance libido, butfound that about 5 mg of amantadine had a similarly beneficial butdistinct effect. The subject described the effect as not seeming to bean androgen mediated effect but rather a “neurogenic” effect thatenhances the readiness for enjoyment of orgasm without a direct effectin libido.

The subject noted that the effect of amantadine seems additive to thatof the PDE5 inhibitor ED drugs. Further, the subject noted that creatineseems to have the effect that a lower dose of a PDE5 inhibitor ED drugworks just as well. Such a result may be by way of an effect on NOproduction.

The subject noted a body weight that varied little from about 78 kg overthe past twenty plus years. The subject noted no use of blood pressureor other prescribed medications on a regular basis.

Memantine is a class of Alzheimer's disease medications acting on theglutamateric system. The IUPAC name is 1-amino-3,5-dimethyl-adamantaneand the molecular weight is about 179 g/mol. A typically dose ofmemantine is in the range of about 5 mg to about 10 mg b.i.d. (twice aday), with a maximum dose of about 20 mg/day.

Memantine is marketed under the brands AXURA®, AKATINOL®, NAMENDA® andEBIXA®. Memantine acts as an uncompetitive antagonist at differentneuronal nicotinic neuronal receptors (nAChRs) at potencies similar tothe NMDA receptor (N-methyl d-aspartate). Memantine also acts as anuncompetitive antagonist at the 5HT₃ receptor (a ligand-gated Na⁺ and K⁺cation channel, resulting in a direct plasma membrane depolarization),with a potency similar to that for the NMDA receptor.

Memantine is generally well-tolerated. Common adverse drug reactions(≦1% of patients) include: confusion, dizziness, drowsiness, headache,insomnia, agitation, and/or hallucinations. Less common adverse effectsinclude: vomiting, anxiety, hypertonia, cystitis, and increased libido.

An exemplary method includes treating urologic problems with memantine.An exemplary method includes treating urologic problems with memantineand creatine. An exemplary method includes treating erectile dysfunctionwith memantine and a PDE5 inhibitor, and optionally creatine. Anexemplary method may include treatment with memantine and amantadine,optionally with creatine and/or a PDE5 inhibitor. In the aforementionedmethods that include administration of creatine, the amount of creatinemay be a CSUE dose level.

An exemplary composition includes creatine and memantine (e.g., pill orother form). An exemplary composition includes memantine and a PDE5inhibitor (e.g., pill or other form). An exemplary composition includescreatine, memantine and a PDE5 inhibitor (e.g., pill or other form). Anexemplary composition includes creatine, memantine, amantadine and aPDE5 inhibitor (e.g., pill or other form). In the aforementionedcompositions that include creatine, the amount of creatine may be a CSUEdose level.

Creatine and Reductase Inhibitors

Adverse drug reactions (ADRs) experienced with 5α-reductase inhibitorsare generally dose-dependent. Common ADRs include impotence, decreasedlibido, decreased ejaculate volume. 5α-reductase inhibitors are a groupof drugs with antiandrogenic activity, used in the treatment of benignprostatic hyperplasia and androgenic (or androgenetic) alopecia. Thesedrugs decrease the levels of available 5α-reductase prior totestosterone binding with the enzyme, thus reducing levels ofdihydrotestosterone that derives from such a bond. 5α-reductaseinhibitors are clinically used in the treatment of conditions which areexacerbated by dihydrotestosterone. Specifically, these indications mayinclude: mild-to-moderate benign prostatic hyperplasia and androgenic(or androgenetic) alopecia. Drugs include finasteride (PROSCAR® andPROPECIA®) and dutasteride (AVODART®).

The enzyme 5α-reductase is involved in the conversion of testosterone tothe active form dihydrotestosterone by reducing the Δ4,5 double-bond. Inbenign prostatic hyperplasia, dihydrotestosterone acts as a potentcellular androgen and promotes prostate growth-inhibiting the enzymereduces the excessive prostate growth. In alopecia, pattern-baldness isone of the effects of androgenic receptor activation. Reducing thelevels of dihydrotestosterone thus reduces alopecia.

An exemplary method includes administration of creatine and a5α-reductase inhibitor. Such a method may contribute to enhancedurogenital function by way of gradual reduction of BPH. An exemplarycomposition includes creatine and a 5α-reductase inhibitor. An exemplarymethod includes administration of creatine and a 5α-reductase inhibitorto reduce one or more ADRs. For example, as already noted, a known ADRof finasteride is ED. Thus, an exemplary method may administer creatineto reduce ED associated with finasteride. The amount of creatine in amethod and/or a composition may be a CSUE does level.

Creatine and ACE Inhibitors

ACE inhibitors, or inhibitors of Angiotensin-Converting Enzyme, are agroup of pharmaceuticals that are used primarily in treatment ofhypertension and congestive heart failure, in most cases as the drugs offirst choice. Sulfhydryl-containing ACE inhibitors include captopril(CAPOTEN®); dicarboxylate-containing ACE inhibitors include enalapril(VASOTEC®/RENITEC®), ramipril (ALTACE®/TRITACE®/RAMACE®), quinapril(ACCUPRIL®), perindopril (COVERSYL®), lisinopril(LISODUR®/LOPRIL®/PRINIVIL®/ZESTRIL®) and benazepril; andphosphonate-containing ACE inhibitors include fosinopril (MONOPRIL®).

An exemplary method includes administration of creatine and an ACEinhibitor. Such a method may gradually reduce urogenital vascularinsufficiency by way of increased physiologic vascular compliance,possibly as a result of increased NO production. An exemplarycomposition includes creatine and an ACE inhibitor. The amount ofcreatine may be a use of CSUE dose level.

Creatine and Angiotensin II Receptor Antagonists

ACE inhibitors share many common characteristics with another class ofcardiovascular drugs called angiotensin II receptor antagonists, whichare often used when patients are intolerant of the adverse effectsproduced by ACE inhibitors. ACE inhibitors do not completely prevent theformation of angiotensin II, as there are other conversion pathways, andso angiotensin II receptor antagonists may be useful because they act toprevent the action of angiotensin II at the AT1 receptor.

An exemplary method includes administration of creatine and anangiotensin II receptor antagonist. Such a method may gradually reduceurogenital vascular insufficiency by increasing physiologic vascularcompliance, possibly as a result of increased NO production. Anexemplary composition includes creatine and an angiotensin II receptorantagonist. The amount of creatine in a method and/or a composition maybe a CSUE dose level.

Some Examples of Other Compounds

With respect to other compounds, a study by Barqawi et al., “Herbal andvitamin supplement use in a prostate cancer screening population”Urology, 2004 Feb; 63(2): 288-92, studied patients using multivitaminsand/or herbal supplements. Such multi-vitamins and/or supplements areoptionally used in connection with creatine.

In particular, the study of Barqawi et al. reported most participants astaking multivitamins, selenium, or herbal supplements. The use of herbalagents such as saw palmetto and Urtica dioica for the treatment of LUTS,and the use of selenium, vitamin E, and phytoestrogens to prevent andtreat prostate cancer, has become more popular in recent years. Sawpalmetto (Latin name Serenoa repens) is fast becoming the most commonlyused herb for the treatment of BPH. As reported in the study of Barqawiet al., controlled clinical trials on saw palmetto suggested that sawpalmetto improves urologic symptoms and flow measures and was associatedwith fewer side effects compared with finasteride. It has beenhypothesized that the mechanism of action of saw palmetto may be due tosuppression of prostatic dihydrotestosterone levels by the inhibition ofthe enzyme 5α-reductase (see, e.g., finasteride).

The second most commonly used herbal extract in benign prostatichyperplasia (BPH) treatment is an extract of Pygeum africanum, anevergreen tree of the Rosaceae family indigenous to Africa. As reportedin the study of Barqawi et al., controlled trials involving 1562 men whoreceived Pygeum africanum for the treatment of BPH indicated that thistreatment provided moderate improvement in the combined outcome ofurologic symptoms and flow measures.

An exemplary composition includes creatine and saw palmetto. Anexemplary method includes administering a composition that includes acreatine and saw palmetto. An exemplary method includes administeringcreatine and saw palmetto.

Another exemplary composition includes creatine and an extract of Pygeumafricanum. An exemplary method includes administering such acomposition. An exemplary method includes administering creatine and anextract of Pygenum africanum.

An exemplary composition includes creatine, saw palmetto and an extractof Pygenum africanum. An exemplary method includes administering such acomposition. An exemplary method includes administering creatine, sawpalmetto and an extract of Pygeum africanum.

An exemplary composition includes creatine and an herb or herb extract.An exemplary method includes administering such a composition. Anexemplary method includes administering creatine and an herb or herbextract.

An exemplary composition includes creatine and an extract from anevergreen species. An exemplary method includes administering such acomposition. An exemplary method includes administering creatine and anextract from an evergreen species.

Other exemplary compositions may include lycopene. The younger subjectobserved that, on occasion for one day at a time, a lack of nocturnalurine stream slowing. Lycopene is present in tomato products while otherfoods of interest include certain beans and blue berries. An exemplarymethod includes administering such a composition. For example, acomposition that includes creatine and lycopene may be administered to asubject to treat a urologic disorder. An exemplary method includesadministering creatine and lycopene to treat a urologic disorder.

DHEA

Another exemplary composition includes dehydroepiandrosterone (DHEA),which is one of the hormones produced by the adrenal glands. After beingsecreted by the adrenal glands, it circulates in the bloodstream asDHEA-sulfate (DHEAS) and is converted as needed into other hormones.Supplementation with DHEA-S (a form of DHEA) has resulted in increasedlevels of testosterone and androstenedione, two steroid hormones.

The conversion of DHEA into testosterone may account for the fact thatlow blood levels of DHEA have been reported in some men with erectiledysfunction. The findings of a double-blind trial using 50 mgsupplements of DHEA taken daily for six months suggests that DHEA mayimprove erectile function in some men.

An exemplary composition includes creatine and DHEA. For example, adaily dose for such an exemplary composition may include about 0.09 g ofcreatine and about 2 mg of DHEA.

According to various exemplary compounds, compositions and methodsdescribed herein, a link exists between nocturnal erectile function andurethral sphincter function. In general, an exemplary composition thatincludes creatine may be enhanced by including another compound thatpromotes nocturnal erections. Noting, that by itself, in an exemplaryrange of about 22 mg to about 0.44 g (440 mg) per day for an adult maleweighing around 80 kg, creatine can increase incidence of nocturnalerections.

An exemplary method includes administration of DHEA in a range of about0.5 mg to about 5 mg a day for a body weight of about 80 kg (about 0.006mg/kg/day to about 0.06 mg/kg/day). Such a method is optionally combinedwith a method that administers creatine where creatine may beadministered at a CSUE dose level.

The younger subject (age about age 57) ingested progressively smallerdoses DHEA alone and in combination with creatine in CSUE doses toinvestigate possibly additive effects. Combination of 1 mg of 2 mg ofDHEA had beneficial effects on urogenital function for one day but hadnegative effects on urinary symptoms thereafter despite lingeringbeneficial effects on sexual function up to 3 to 4 days. It isspeculated that the low DHEA dose temporarily increases testicularproduction of testosterone whereas larger doses directly inhibit FSHproduction.

A possible concern about using DHEA to enhance urogenital function isthat it may provide a substrate to increase endogenous androgensynthesis by prostatic tissue, thereby promoting BPH. Thus, where such aconcern exists, then use of DHEA may be avoided or sufficiently reduced.Monitoring may be performed to assess such a concern.

An exemplary method to treat urinary flow-related symptoms includesincreasing the number of nocturnal erections. As described herein, suchan exemplary method may increase the number of nocturnal erections byany of a variety of means. For example, an increase in nocturnalerections may be achieved through use of creatine at CSUE dose levels.

Dosing

An exemplary container or dose delivery system includes tablets ofcreatine monohydrate and optionally one or more other compounds (see,e.g., aformentioned compounds). For example, a container may containtablets with about 100 mg creatine monohydrate per tablet. Such tabletsare optionally shaped to provide for halving to about 50 mg. Anexemplary method includes administering about 3 of the tablets per dayduring a loading phase and then about 1 tablet per day during amaintenance phase. The weight of an active(s) in a tablet may beselected according to one or more CSUE dose levels.

An exemplary container or dose delivery system includes tablets thatinclude creatine monohydrate and DHEA. For example, a tablet may includeabout 100 mg creatine monohydrate and about 1.0 mg DHEA. An exemplarymethod includes administering about 3 of the tablets per day during aloading phase and then about 1 tablet per day during a maintenancephase.

An exemplary container or dose delivery system includes tablets thatinclude creatine monohydrate and a PDE5 inhibitor. For example, a tabletmay include about 100 mg creatine monohydrate and about 25 mg ofsildenafil citrate. An exemplary method includes administering a tabletprior to sexual intercourse (e.g., about 4 hours prior to about 30minutes prior to sexual intercourse).

An exemplary container or dose delivery system may be a bottle, afoil-pack, or other conventional package. As already mentioned, forathletic purposes, creatine monohydrate is supplied conventionally as apowder in a bottle where a dose size is greater than 2 g (CSR dose). Asdescribed herein, relief of certain urologic symptoms is dependent ondose size and dose size is less than 2 g (e.g., CSUE dose). Thus, theexemplary dose delivery systems that easily allow for adjustment ofdoses in a ratio of about 10:1 (e.g., 50 mg to 500 mg or 25 mg to 250mg, etc.) have advantages over the conventional powder in a bottlepackage, especially where a loading phase is beneficial. Further,tablets may be shaped to facilitate dose size reduction. For example, a100 mg tablet may be shaped to be easily broken into two 50 mg tablets.

FIGS. 1A, 1B and 1C show various arrangements for dose delivery. FIG. 1Ashows a dose delivery system with two packages 101, 101′ wherein thepackage 101 contains a dose 102 and the package 101′ contains a dose102′ where the dose 102 is larger than the dose 102′. For example, thesystem of FIG. 1A may include a loading package 101 with a loading dose102 and a maintenance package 101′ with a maintenance dose 102′. Notethat the doses 102, 102′ may include indicia for halving.

In another example, the two packages 101, 101′ of FIG. 1A may includedifferent compounds and/or compositions. For example, the package 101may include a dose 102 of creatine monohydrate (e.g., a CSUE dose) andthe package 101′ may include a dose 102′ of a PDE5 inhibitor (e.g.,sildenafil citrate, vardenafil, tadalafil). A subject may then select totake a dose 102 and a dose 102′ simultaneously or at different times. Asubject may select to take a dose 102 on a daily basis and a dose 102′prior to sexual activity (e.g., intercourse or other sexual activity).In general, where sexual intercourse is mentioned in this description,other sexual activity may substitute for intercourse.

In yet another example, more than two packages may be supplied in asingle product package (e.g., a box). For example, a box may include apackage for creatine, a package for amantadine and a package for a PDE5inhibitor.

FIG. 1B shows a dose delivery system that includes a lidded container103 and pills or tablets 104. The pills or tablets 104 may be gel,compressed powder, etc., and optionally include indicia or othermechanism to allow for division (e.g., halving). The pills or tablets104 may include creatine monohydrate and optionally another compound(e.g., sildenafil citrate, amantadine, etc.).

FIG. 1C shows a dose delivery system sometimes referred to as a foilpack where a foil pack 105 includes individual doses 106. Such doses maybe gel, compressed powder, etc., and optionally include indicia or othermechanism to allow for division (e.g., halving).

An exemplary kit may be a so-called blister pack. Blister packs are wellknown in the packaging industry and are wildly used for the packaging ofpharmaceutical unit dosage forms such as tablets, capsules, and thelike. Blister packs generally consist of a sheet of relatively stiffmaterial covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably, the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. Tablet(s) or capsule(s) can then be removed viathe opening.

It may be desirable to provide a memory aid on a kit, e.g., in the formof numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen during which the tablets orcapsules so specified should be ingested. Another example of such amemory aid is a calendar printed on the card, e.g., as follows “FirstWeek, Monday, Tuesday, . . . , etc . . . Second Week, Monday, Tuesday, .. . ”, etc. Other variations of memory aids are possible. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day or at a given time prior to sexual activity. Insome instances, one dose of a compound or composition may be of a lessfrequent basis than a dose of another compound or composition. Forexample, creatine monohydrate at a CSUE dose may be daily while a PDE5inhibitor dose may be just prior to sexual activity. Also, a daily doseof the first compound may be one table or capsule while a daily dose ofthe second compound may be several tablets or capsules and vice versa. Amemory aid may reflect one or more of such variations.

One or more other pharmaceutical components may also be optionallyincluded as part of an exemplary compound and/or composition so longinterference or adverse effects are avoided with intended treatment of aurologic disorder or disorders.

The following formulation examples are illustrative only and are notintended to be limiting. In the formulations which follow, “activeingredient” means a compound(s), as discussed herein (e.g., creatinemonohydrate, PDE5 inhibitor, adamantane derivative, etc.). In theformulations 1, 2 and 3, the active ingredient may be increased beyond100 mg, if so desired. For example, a PDE5 inhibitor dose may be about50 mg and a creatine monohydrate dose about 100 mg, hence, the activeingredient may be about 150 mg for this example. Adjustments to theother ingredients may be made accordingly (e.g., using ratios or othercalculations), if required.

Formulation 1: Gelatin Capsules

Hard gelatin capsules are prepared using the following ingredientquantity (mg/capsule):

Active ingredient 0.25-100   Starch, NF  0-650 Starch flowable powder0-50 Silicone fluid 350 centistokes 0-15

Formulation 2: Tablets

A tablet formulation is prepared using the following ingredientsquantity (mg/tablet) where the components are blended and compressed toform tablets:

Active ingredient 0.25-100  Cellulose, microcrystalline 200-650 Silicondioxide, fumed  10-650 Stearate acid  5-15

Formulation 3: Tablets

Another tablet formulation is for tablets as follows where ingredientquantity is given as mg/tablet:

Active ingredient 0.25-100 Starch 45 Cellulose, microcrystalline 35Polyvinylpyrrolidone (as 10% sol'n H₂O) 4 Sodium carboxymethyl cellulose4.5 Magnesium stearate 0.5 Talc 1

In this example, the active ingredient, starch, and cellulose are passedthrough a No. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

While powder and tablets have been discussed, other forms for creatinemonohydrate or other compounds include, but are not limited to,unencapsulated gel and liquid forms. Other forms may be in the form of apatch (e.g., for transdermal delivery), a suppository, etc. In general,a pharmaceutically acceptable vehicle, diluent or carrier may be used.

Indexes

An exemplary method comprises administering a test to a patient and theprescribing an exemplary composition (e.g., creatine monohydrate,amantadine and/or ED drug, etc.) based at least in part on the test. Atest may assess lower urinary tract symptoms (LUTS), which are moregenerally urologic symptoms (noting that impotence, erectiledysfunction, etc., are also urologic symptoms). For assessment of lowerurinary tract symptoms several instruments have been developed. Mosttests describe frequency of symptoms as a first basic step towardunderstanding patient condition.

The Boyarsky Score is a questionnaire to assess lower urinary tractsymptoms. The questionnaire is designed to be completed by thephysician. The symptom scoring system evaluates the severity ofnocturia, frequency, hesitancy, intermittency, terminal dribbling,urgency, reduction of the size and force of the stream, dysuria andincomplete voiding.

The Madsen-Iversen Score is another questionnaire, also designed forcompletion by the physician. The questionnaire assesses urinary stream,straining to void, hesitancy, intermittency, bladder emptying, stressincontinence or post void dribbling, urgency, frequency and nocturia.The importance of the patient's perception of the symptoms has beenrecognized and new instruments for assessing severity, frequency andquality of life of lower urinary tract symptoms have been designed.Health measurements or scales can be used to directly inquire about theimpact of the symptoms or the distress they cause.

The International Prostate Symptom Score (IPSS) questionnaire is avalidated instrument that measures the occurrence of seven symptoms fromthe lower urinary tract (incomplete emptying, frequency, urgency,nocturia, straining, weak stream, hesitancy). The IPSS questionnaireincludes one separate question concerning the quality of life, graded ona scale from 0 to 6.

The American Urologic Association (AUA) symptom index is a validatedquestionnaire and includes seven questions covering frequency, nocturia,weak urinary stream, hesitancy, intermittence, incomplete emptying andurgency and two questions on quality of life.

The ICSmaleSF questionnaire includes 11 questions on lower urinary tractsymptoms (hesitancy, straining, decreased stream, intermittency,incomplete emptying, urgency, urge incontinence, stress, incontinence,unpredictable incontinence, nocturia, post-void dribbling) and onequestion on quality of life.

The Danish Prostatic Symptom Score (DAN-PSS) measures the occurrence of12 symptoms. Moreover, it evaluates the symptoms both quantitatively andqualitatively, using both a symptom score and a distress score. Thisinstrument has a sensitivity of 92% and a specificity of 94%. TheDAN-PSS questionnaire also measures the occurrence of dysuria, postmicturition dribbling and urinary incontinence, as well as measuringactivities of daily living, none of which are covered by the IPSSquestionnaire. The DAN-PSS questionnaire is well understood by men 40years or older and is reliable and valid for the same purposes as theIPSS questionnaire. The Spearman correlation coefficient between theprevalence as measured with DAN-PSS and IPSS was 0.75 and thecorrelation coefficient between total DANPSS score and total IPSS scorewas 0.70.

Some Exemplary Methods, Compounds, Compositions, etc.

Various exemplary methods, compounds, compositions, dosing techniques,etc., are discussed herein. An exemplary method includes administering adaily dose of creatine to an individual wherein the daily dose lies in arange from about 0.35 mg to about 3.5 mg per kilogram body weight. Anexemplary dose delivery system includes individual doses of creatinewherein the individual dose comprises 88 mg or less of creatine and acontainer to contain the doses.

An exemplary method of treating a urologic symptom includesadministering a daily dose of creatine to an individual wherein thedaily dose lies in a range from about 0.35 mg to about 3.5 mg perkilogram body weight. Such a method may further include administering adose of a compound that inhibits phosphodiesterase at a time prior tosexual activity (e.g., less than approximately 4 hours). In thisvariation, the compound that inhibits phosphodiesterase may optionallybe one or more of the following sildenafil, vardenafil, tadalafil.

An exemplary method of treating a urologic symptom includesadministering a daily dose of creatine and administering a dose of acompound that includes DHEA. In this example, the method may administera daily dose of a compound that includes DHEA. The dose of DHEA may liein a range from about 0.006 mg to about 0.06 mg per kilogram bodyweight.

An exemplary method of treating a urologic symptom includesadministering a daily dose of creatine and administering a dose of acompound derived from adamantane. For example, the compound derived fromadamantane may optionally be one or more of amantadine, memantine andrimantadine.

An exemplary method of treating impotence includes administering to apatient in need of such treatment an effective amount of creatine and acompound which elevates cGMP levels. In such an example, creatine and acompound which elevates cGMP levels may be each administered orally. Inother examples, creatine and/or a compound which elevates cGMP levelsmay be administered other than orally. In the foregoing method, the cGMPelevator may be a cGMP PDE inhibitor. In the foregoing example, the cGMPelevator may be a prostaglandin.

An exemplary method of treating impotence includes administering to apatient in need of such treatment an effective amount of (1) creatinewherein the effective amount of creatine lies in a range fromapproximately 0.35 mg to approximately 3.5 mg per kilogram body weightof the patient and a compound which elevates cGMP levels. In such anexample, creatine and a compound which elevates cGMP levels may be eachadministered orally. In other examples, creatine and/or a compound whichelevates cGMP levels may be administered other than orally. In theforegoing method, the cGMP elevator may be a cGMP PDE inhibitor. In theforegoing example, the cGMP elevator may be a prostaglandin.

An exemplary method of treating impotence includes administering to apatient in need of such treatment an effective amount of creatine and acompound which elevates cGMP levels such as a cGMP PDE inhibitorselective for the cGMP PDE5 isoenzyme. In this example, the cGMP PDE5inhibitor may be sildenafil or a pharmaceutically acceptable saltthereof (e.g., a citrate salt).

In various examples, compounds may be administered together in acomposition. For example, any of the foregoing creatine and othercompound(s) may be administered together in a composition. As analternative, or in addition to, creatine and other compound(s) may beadministered separately. For example, creatine may be administered dailyand another compound administered prior to sexual intercourse (e.g.,less than approximately 4 hours prior to sexual intercourse).

An exemplary method of treating impotence includes administering to apatient in need of such treatment an effective amount of creatine, acompound which elevates cGMP levels and a compound derived fromadamantane. For example, the compound derived from adamantane mayoptionally be one or more of amantadine, memantine and rimantadine.

An exemplary composition includes creatine and a compound that inhibitsphosphodiesterase. Such a composition may be a powder, a solid, a gel, aliquid, etc. An exemplary composition may include creatine together withand sildenafil, vardenafil and/or tadalafil.

An exemplary composition includes phosphorylate creatine, a compoundthat inhibits phosphodiesterase and a compound derived from adamantine.An exemplary composition may include creatine together with andsildenafil, vardenafil and/or tadalafil and a compound derived fromadamantane.

1. A method of treating nocturia in a human individual comprising administering a daily dose of creatine to the individual wherein the daily dose of creatine lies in a range from about 0.35 mg to about 3.5 mg per kilogram body weight; and administering a dose of amantadine.
 2. The method of claim 1 wherein the dose of amantadine comprises about 0.0625 mg amantadine per kilogram human body weight of the individual.
 3. The method of claim 1 wherein the administering creatine and the administering amantadine comprises administering the creatine and the amantadine orally.
 4. A method of treating nocturia in an adult human individual comprising administering orally a daily dose of creatine to the individual wherein the daily dose of creatine lies in a range from about 0.35 mg to about 3.5 mg per kilogram body weight; and administering orally a dose amantadine wherein the dose of amantadine comprises about 0.0625 mg amantadine per kilogram human body weight of the individual. 